It is well known in the art that it is desired to have compositions adapted to be orally administered to ruminants and which are beneficial to ruminants after passing the rumen and reaching a post-rumen site, e.g., the abomasum and/or intestines.
In ruminants, ingested feed first passes into the rumen, where it is pre-digested or degraded by fermentation. During this period of fermentation the ingested feed may be regurgitated to the mouth via the reticulum where it is salivated and ruminated. After a period of fermentation regulated by natural processes and variable depending on the animal and the feedstuff, adsorption of digested nutrients starts and continues in the subsequent sections of the digestive tract by the ruminant animal. This process is described in detail by D. C. Church, "Digestive Physiology and Nutrition of Ruminants", Vol. 1, O.S.U. Book Stores, Inc., of Corvallis, Oreg.
The rumen, the largest of the four stomach compartments of ruminants, serves as an important location of metabolic breakdown of ingested foodstuffs through the action of microorganisms which are present therein. Ingested food is typically retained in the rumen for from about 6 to 30 hours or longer in some instances, during which time it is subject to metabolic breakdown by the rumen microorganisms. Much ingested protein material is broken down in the rumen to soluble peptides and amino acids and utilized by the rumen microorganisms. When the rumen contents pass into the abomasum and intestine, the microbial mass is digested, thus providing protein to the ruminant. Thus, the natural nutritional balance of the ruminant animal is primarily a function of the microbial composition and population.
In preparing nutrients and medicaments intended for administration to ruminants, it is important to protect the active ingredients against the environmental conditions of the rumen, i.e., microbial degradation and the effects of a pH of about 5.5-7.0, so the active substance will be saved until it reaches the particular location where adsorption takes place. It is well known that the rate of meat, wool and/or milk production can be increased if sources of growth limiting essential amino acids, and/or medicaments, are protected from alteration by microorganisms residing in the rumen and become available for direct absorption by the animal later in the gastrointestinal tract.
Materials which protect the bioactive agents, i.e., nutrients and medicaments, against degradation by the rumen contents should be resistant to attack by the rumen fluid which contains enzymes or microorganisms but must make the active ingredient available post-rumenally, e.g., in the abomasum or in the small intestine.
Because proteins are subject to breakdown in the rumen, it has been suggested that protein-containing nutrients fed to ruminants be treated so as to permit passage without microbial breakdown through the rumen to the abomasum. Suggested procedures have included coating the protein material, for example, with fats and vegetable oils or with an acid sensitive coating; heat treating of the protein material; reacting the protein material with various compounds such as formaldehyde, acetylenic esters, polymerized unsaturated carboxylic acid or anhydrides and phosphonitrilic halides, etc.
It is well known that all proteins found in animal and plant life are chemical compounds containing different combinations of over 20 amino acids, the number and arrangement of such acids being fixed in any particular protein. Twelve of these amino acids can be synthesized in nutritionally adequate normally present in most animals, but the remaining 10 essential amino acids are not synthesized in sufficient quantities and must be ingested by the animal. Since the proportions of the constituent amino acids in a particular protein cannot be varied, the essential amino acid least in supply limits the amount of that protein which can be produced by the animal. Consequently, for any given diet, there will be a particular essential amino acid which limits the production of protein incorporating that essential amino acid unless, of course, two or more such amino acids are equally limiting.
The appreciation of the above principles leads to the formulation of diets for nonruminant animals which provide the optimum proportion of amino acids and have enable significant increases in protein production to be achieved. In the ruminant, dietary proteins and amino acids are, to a variable extent, broken down to ammonia and various organic compounds by microbial fermentation in the first two compartments of the stomach (the rumen and reticulum). The bacteria and protozoa in these organs utilize these metabolites for their own growth and multiplication and the microbial protein so formed passes on to the abomasum, the compartment of the stomach corresponding to the stomach of nonruminants, where it is partially digested. The process is completed in the small intestine and the amino acids are absorbed. Therefore in many instances it is desirable to protect certain essential amino acids from the microorganisms of the rumen and reticulum and thus deliver such amino acids to the abomasum and small intestine.
It is likewise well-known that some medicaments are more effective when they are protected from the environment of the rumen. See, for example, U.S. Pat. Nos. 3,041,243 and 3,697,640. See also "Controlled-Release Feed Additives for Ruminants: Cellulose-Based Coating Composition for Rumen-Stable Nutrients," Wu, et al., in Controlled Release of Pesticides and Pharmaceuticals, D. H. Lewis, ed., Plenum Press, New York, N.Y., 1981, p. 319.
The following patents issued to Dannelly et al., teach the art of formulating rumen-stable pellets for a variety of nutrients and medicaments: U.S. Pat. Nos. 4,177,255; 4,181,708; 4,181,709; 4,181,710; and 4,196,187. These patents disclose the art of formulating rumen-stable pellets employing coating techniques. Specifically these patents teach employing a coating process such as air suspension coating to apply a coating formulation onto a solid substrate containing bioactive materials. To practice the technology disclosed in these patents, cores containing medicaments must be prepared first, for example, by a granulation method and then coated with the rumen-stable coating compositions described in the patents. The disclosed technology is particularly useful for preparing a dosage form with high payload of bioactive materials such as amino acids. However, multiple unit operations must be employed to yield the finished products.
U.S. Pat. No. 3,959,493, issued to Baalsrud et al., teaches rumen-stable products comprising biologically active substances protected with aliphatic fatty acids. U.S. Pat. No. 3,655,864, issued to Grass et al., teaches veterinary compositions permitting post-ruminal delivery of biologically active feed additives, in which the compositions are embedded in or coated by an intimate mixture of glyceryl tristearate with a liquid unsaturated higher fatty acid.
U.S. Pat. No. 4,473,545, issued to Drake et al., teaches an animal feed additive comprising a composite of a relatively insoluble binder, a particulate soluble material and an active material. The particulate material is such that it is readily soluble under a particular range of pH conditions, e.g., dissolution rates at pH 2 and pH 6 in the ratio 12:1. Dissolution of the particulate materials rendered the binder water permeable thus permitting release of the active material.
U.S. Pat. No. 4,533,557 teaches a feed additive for ruminants comprising a mixture in tablet or granule form of at least one biologically active ingredient, chitosan and a protective material such as fatty acids having 14 to 22 carbon atoms.
U.S. Pat. No. 3,880,990, issued to Bauer et al., teaches oral ruminant compositions comprising a medicinal substance encapsulated or embedded in a basic polymer. Such compositions are produced by dispersing the medicinal substance in a first solvent in a finely powdered form and adding thereto a second solvent which is immiscible with the first solvent in which the polymer and medicinal substance are substantially insoluble. In such a conventional polymer/medicament dispersion, activity can be lost due to the presence of dispersed active particles at or near the surface of the compositions which will not survive the environment of the rumen. In addition, at some loadings, water channels can form leading to reduced rumen protection of the active particles.
It would be desirable to have rumen stable compositions that avoid multiple step preparatory methods and retain more activity than compositions of conventionally dispersed bioactive particles in a polymer matrix.